Signaling Hierarchies in Vertebrate Development

该计划项目的长期目标是定义脊椎动物胚胎中特定命运的细胞域，并了解这些域是如何最初构思、随后提炼和逐步细分的，以便单个细胞最终可以根据它们的位置表达高度受限的命运。在目前的项目期间，很明显，在每个发育阶段都使用了广泛保守的细胞间信号分子，并且信号相互作用发生在分级级联中。了解这些信号如何作用和相互作用，以及信号层次结构的逻辑，对于理解发育模式至关重要。下一个项目阶段的目标是获得对特定细胞命运和胚胎区域的了解。这一目标将在三个组成部分的项目中实现。基梅尔的项目：形成头盖力的信号；韦斯特菲尔德的项目：形成前中枢神经系统的信号；艾森的项目：神经元指定过程中信号通路之间的相互作用。每个项目都提出了一项基于遗传的斑马鱼发育分析。基因表达分析，以及涉及野生型和突变胚胎之间细胞移植的马赛克分析，将揭示信号细胞和对信号丢失和获得做出反应的细胞，功能实验将在不同的信号之间建立分层相互作用，如结节、刺猬、视黄醇、甲状腺激素和神经营养因子。所有这些信号通路的缺陷，以及将要检查的其他信号通路的缺陷，都与特定的人类疾病有关；因此，这项研究的结果将直接影响人类健康。五个核心设施，包括一个独特的遗传/斑马鱼设施，将为这些组成部分项目提供支持。

The long term goals of this Program Project are to define the domains of cells specified to particular fates in a vertebrate embryo, and to learn how these domains are initially patterned, subsequently refined, and progressively subdivided such that individual cells can finally express highly restricted fates according to their positions. During the current project period it has become apparent that widely conserved intercellular signaling molecules are used at each of the developmental steps, and that the signaling interactions occur in hierarchical cascades. Understanding how these signals act and interact, and the logic of the signaling hierarchy, is critical for understanding developmental patterning. The goal for the coming project period is to obtain this understanding for particular cell fates and regions of the embryo. The goal will be achieved in three Component Projects. Project by Kimmel: Signals that pattern the skull forces; Project by Westerfield: Signals that pattern the anterior central nervous system; Project by Eisen: Interactions among signaling pathways during neuronal specification. Each project proposes a genetically based developmental analysis using zebrafish. Gene expression analysis, and mosaic analyses involving transplantation of cells between wild-type and mutant embryos, will reveal the signaling cells and cells that respond to the signals Loss- and gain-of function experiments will establish hierarchical interactions among signals as diverse as nodals, hedgehogs, retinoids, thyroid hormones, and neurotropic factors. Defects in all these signaling pathways, as well as others that will be examined, are implicated in particular human diseases; hence, results from this research will have direct bearing on human health. Five Core Facilities, including a unique Genetics/Zebrafish Facility, will provide support for these Component Projects.